Dual drug approach shows promise against childhood cancer

Cambridge scientists have developed a promising new treatment for the most common childhood cancer. The approach combines two drugs to target B-cell acute lymphoblastic leukaemia - or B-ALL. Simon Richardson, from the Cambridge Stem Cell Institute, noticed that cancers carrying a mutation in a gene called CREBBP produce much more aggressive disease. But, by introducing this change into cancer cells grown in the lab, he also found that they become exquisitely sensitive to a chemotherapy drug called venetoclax. And then he found another drug that can put all cells into this sensitive state, not just the ones with the mutation. So, by dosing a tumour with both agents, you can kill all of the cells. It could, if the forthcoming clinical trial works, significantly cut treatment regimes, and improve remission rates for people with the disease.

Simon - B-ALL is a highly aggressive cancer of B-cell immune cells in the bone marrow. These cells normally would go ahead to produce antibodies in your blood to protect you against infection but they're too primitive to actually be useful so they build up in the bone marrow stopping you from producing normal blood which is very dangerous, could make you have infections, tiredness and bleeding. And then they can move around the body and they can enter places like the brain where they can hide from chemotherapy.

Chris - And how do we currently try and manage the condition?

Simon - So the good news is in children this is a treatable condition but the treatment is two years of chemotherapy so it's quite intensive. So the majority of children are cured but as you get older the treatment becomes more toxic and less effective and fortunately in adults we end up using bone marrow transplantation for the majority of adults and it's got about a 50% cure rate. So we need more effective treatments particularly for adults and kinder treatments for children.

Chris - So how have you progressed towards that? What have you actually been doing?

Simon - So we've been very interested in a gene called CREBBP. This gene was picked up a few years ago as being associated with resistance to chemotherapy and is highly enriched in patients who relapse with this disease.

Chris - Right, so this is a marker that if they've got that particular change to that particular gene it's probably bad news for the disease?

Simon - Yeah there's something about this gene that this disease really likes and it makes the cells much more resistant to current treatments like chemotherapy.

Chris - Which you're thinking then that if you can get underneath what that gene's doing then that may unlock a better way to treat it?

Simon - That's right. So what we did was to take cell lines that were derived from patients with this leukaemia and we used a genetic engineering approach to introduce this mutation into those cell lines. So we had cell lines that just differed by this one mutation.

Chris - As in when you say cell lines, cells cultured in a dish, you're engineering in that change. So you basically have got in a dish what would be going on in that patient's bone marrow?

Simon - Exactly. One leukaemia from one patient split into two, one with a mutation one without.

Chris - How do you then use that to work out how to manage that disease better then?

Simon - So we started looking at the differences between these cell lines and in particular for this project we were looking at how they responded to different drugs and the big surprise to us was that these cells became really sensitive to a drug called venetoclax.

Chris - What does that mean in terms of therapy?

Simon - We found that there was another drug called Inabrodib and that drug can actually mimic the effect of this CREBBP mutation and when we put that on the cells, although they didn't mind it in itself, it made them much more sensitive to the Venetoclax.

Chris - That's ingenious. So you're basically mimicking the effect of the mutation with the other drug which is a bit like sort of something that opens the door so that the other drug can lob a bomb in and blow the cell apart. So you use a one-two punch almost like that.

Simon - Yeah, so it's either we call it synergy or sensitisation, depends on whether the cells are already sensitive to it or not, but it works across all sorts of different genetic subtypes of ALL. We think it will mean that many more patients can benefit from venetoclax and for much longer and we've got it to a stage where we'd be interested now to test it in patients. Chris - And is that what is on the cards?

Simon - Yep, so we have applied for clinical trial funding to test these two medications in adults and in teenagers.

Chris - One of the problems with cancer is that it mutates. It evolves all the time to sidestep the immune system, to sidestep drugs. So what's not to say that it won't just sidestep this? You might buy some time but after a while we're back to square one.

Simon - You're totally right. So the key with cancer is to target different ways of killing the cells and the current treatment that we use is chemotherapy which targets cells that are cycling very quickly and we use immunotherapies which target the immune system against these leukaemic cells. The really attractive thing about this particular approach is it's completely different to either of those and potentially quite complementary to them as well. So that might allow us to reduce the doses of traditional chemotherapy therefore reducing the toxicity.